Objective 6 Draw conformational isomers of chains (staggered, eclipsed) and rings (chair – axial/equatorial, boat, cis/trans) using •  skeletal structures, •  Newman projections, •  wedge-dash, •  sawhorse. Identify most stable conformer.

Molecules Are NOT Static Structures! Molecular dynamics simulation of a drug entering into the binding site of a target protein (http://www.youtube.com/watch?v=ckTqh50r_2w)

First Spontaneous Ligand Binding Simulated (http://www.youtube.com/watch?v=8xQtaWEroWM)

Molecules Are NOT Static Structures! Molecular motor turns rotor

http://cen.acs.org/articles/95/i23/Molecular-motor-turns-rotor.html

Molecular Switches involve conformational change https://www.youtube.com/watch?v=loaqIqKCmog

http://cen.acs.org/articles/92/i35/Aiming-HIVs-Weak-Spot.html

How is Stereochemistry Involved?

A Structure Looks Static But A Molecule Is Dynamic Conformational Analysis - bonds vibrate (stretch and bend). Repulsion of electrons (lp/bp) distorts (strains) a molecule from ideal shape/angle --> Destabilizes molecule. Steric: through space. Inductive: through bonds Steric strain consists of angle, torsional, and Van der Waals strain. Angle strain: distortion of a bond angle from ideal angle Torsional Strain: repulsion between pairs of bonds caused by the electrostatic repulsion of the electrons in the bonds. Van der Waals strain: repulsion between electron clouds in atoms or groups Ring Strain: ring is less stable than chain due to angle and torsional strains. The extra energy released when a ring is broken.

Inductive vs. Steric Which one is like a steric effect?

�too close - get out of my face!�

�Don�t pull too hard!�

Alkane Chains: Staggered Conformer is More Stable Steric Strain within Molecule Causes Rotation about the C-C σ Bond Conformational Isomers (Conformers) have different stabilities. Conformer types: staggered/anti/gauche (more stable) and eclipsed/syn (less stable) http://www.chem.ucalgary.ca/courses/351/Carey5th/Ch03/ch3-03.html Conformers are represented by:

Which atoms are causing the strain?

Objective: identify the most stable conformer Which conformational isomer is the most stable?

Propane

Ethane:

Which conformational isomer is the most stable?Ethane:

Propane

Butane

Isobutane

Which conformational isomer is the most stable?Ethane:

Propane

Butane

Isobutane

Objective: identify the most stable conformer Which conformational isomer is the most stable?

Butane

Isobutane

Which conformational isomer is the most stable?Ethane:

Propane

Butane

Isobutane

Objective: draw Newman, wedge-and-dash, sawhorse representations Draw the wedge-and-dash, sawhorse, and Newman projection of the conformers of n-C5H12 and 2-methylbutane. Identify the most stable isomer. Staggered - anti and gauche Eclipsed – syn

Draw the wedge-and-dash, sawhorse, and Newman projection of the conformers of n-C5H12 and 2-methylbutane. Identify the most stable isomer.

Wedge-and-dash

Sawhorse

Newman projection

Sight along a specific C-C bond, e.g., C2-C3

H

H

H

H

C2H5

H3C

CH3

H

H

H

CH3

H3C

O

https://cen.acs.org/sponsored-content/burgeoning-cannabis-market-brings-new-opportunities.html

CBD – no psychogenic effects Possible medicinal: analgesic, anti-inflammatory, antianxiety properties Which bond rotates in CBD to form THC?

THC– intense psychogenic effects

Objective: Which conformer is more stable?

a b

cyclohexane

Hint: draw in the H’s. Which H’s are closest (repulsion)?

Alkane Rings: Chair Conformer is More Stable Steric Strain Leads to Different Ring Conformers

Conformers for cyclohexane: chair and boat (and twist boat) Substituents: axial and equatorial Which conformer is more stable? Why? Which atoms are causing the strain?

Draw the Newman projection of the boat conformer.

Objective: Which conformer is more stable?

Methylcyclohexane

Substituted cycloalkane rings (Klein, 1st ed., p. 172) �the equilibrium between the two chair conformations will generally favor the conformation with the equatorial substituent.�

Di (or poly) Substituted cycloalkane rings: Cis and Trans Wedges - up (above the ring) Dashes - down (below the ring) 2 substituents: Cis - same side of ring Trans - opposite sides of ring

Which methyl group is above the ring? Which methyl group is below the ring?

Trans-1,4-dimethyl cyclohexane

Di-Substituted cycloalkane rings: Cis and Trans Wedges - up (above the ring) Dashes - down (below the ring) 2 substituents: Cis - same side of ring Trans - opposite sides of ring 1,4-dimethylcyclohexane is shown below. Which structures are trans? Draw the chair conformer to confirm. Which are isomers? Which are the same?

Select the compounds in each group that are isomers and specify whether they are constitutional isomers or stereoisomers.

3/30/15, CEN, p. 5 “Most polar non-ionic compound” All-cis hexafluorocyclohexane Dipole moment = 6.2 Debyes Draw the chair conformer.

7/27/15, CEN, p. 4 Letters: “Debating Most Polar” Dipole moment = 9.2 Debyes Effective conjugation of 2 pairs of dimethylamino and aldehyde groups

http://cen.acs.org/articles/93/i13/Molecule-Claims-Polar-Title.html

Is the ring in the chair or boat conformer? Is this molecule polar or non-polar?

Biomolecules Contain Rings: What is the most stable conformer of each compound?

Also, see http://www.chem.ucalgary.ca/courses/351/Carey5th/Ch03/ch3-10.html

The carbohydrate shown here is a component of a drug used in veterinary medicine. Which is the most stable pyranose conformation?

Heterocyclic compounds: rings than contain atoms besides C Do these heterocyclic compounds have conformers? If so, which conformer is the most stable?

�Examining Explosives�, C&EN, 7/18/11, p. 32 Energetic material: combination of oxidizer and fuel. E.g., in TNT, O in nitro groups = oxidizer, C = fuel �Low� explosives propagate energy relatively slowly by burning. E.g., gunpowder and fireworks. �High� explosives detonate though a shock front that propagates at 5-10 km/sec. E.g., TNT, peroxides HMX has 2 crystal forms: chair β form at r.t. and boat δ form at 165oC. δ form explodes more violently than β form.

Cubane is studied as a Fuel and Explosive (Carey, 8th ed., p. 134, 3.37)

What is the chemical formula of cubane? Does cubane have conformers? If so, what is the most stable conformer? What type of strain is involved in cubane? Why do you think cubane is a fuel and explosive? How many rings are in cubane? (see Carey, 8th ed., p. 124)

Cubane synthesis (http://en.wikipedia.org/wiki/Cubane) involves Diels-Alder reaction (see conjugated dienes, Ch. 10.15)

Polycyclic Rings Are Found in Natural Products

Do these compounds have conformers? If so, which conformer is the most stable? Are any of these compounds planar?

Polycyclic Rings Are Found in Natural Products (+)-Phorbol is found in the sap of the manchineel tree. The sap can cause skin to blister on contact. Phorbol esters encourage tumors to grow rapidly. Phorbol compounds show promise as immune-modulating, antiviral, anticancer therapies.

How many rings? Which ring(s) have conformers?

Preussomerins are a novel class of fungal metabolites that share a stable bis-spiroacetal ring system and are related to naphthalenediol-derived spiroacetals that show a wide range of biological activities. (CEN, 5/24/99, p. 30)

Are the four rings in the same plane?

https://cen.acs.org/physical-chemistry/chemical-bonding/Chemists-claim-ve-defined-first/96/i22

New class of stereoisomers? Akamptisomers – bond angle inversion in which the central atom in a bent, singly bonded trio of different atoms flexes in the opposite direction.

For other isomer, see https://cen.acs.org/is/content//content/dam/cen/96/22/09622-scicon3-inversion.gif

Possible applications: drug molecules, molecular switches

B=pink O=red Porphyrin ring